Epigenetics as a biochemical record of life events. Flashcards
How do the three contrasting honeybee phenotypes develop.
- Two identical diploid embryos develop either into a functionally sterile and short-lived female worker, or into a highly reproductive and long-lived queen, depending on dietary intake during postembryonic development.
- Male drones develop from unfertilised haploid eggs laid by the queen in special cells. While sex determination is genetically controlled, drone larvae receive a distinct diet in larger quantities compared to workers, suggesting that like queens, nutrition provides important cues for proper development.
What are the differences between the nurse and forager worker subcastes in terms of gene expression in the brain? Artificial phenotypic switching - hive trickery (Herb et al., 2012). How does this contrast with the difference between the irreversable worker and queen castes? What does this suggest?
Worker bees go from nurse caste to the forager caste during their adult lives -> phenotypically very different behaviour. Taken brains from both castes and found global differences in the DNA methylation of the samples. No difference in methylation between workers and queens, thereby suggesting that DNA methylation underlies the labile behavioural phenotype of drones.
How and why do epigenetic changes occur between twins over time?
Twins are analogous to totipotent cells. Identical twins have identical DNA. At 3 years equal DNA methylation.
Some areas will be hypermethylated, some areas will be hypomethylated. Global differences in epigenetic status increased between twin pairs who were older, spent less time together or had different medical histories (Fraga et al., 2005).
Do different lives give rise to different patterns of epigenetic markers? How can this be used? ASD discordance. Childhood psychosis –> schizophrenia (Dempster et al., 2011), only 10% differences implication
- Used to explore if twins can be differentially vulnerable to disease types and whether this is underpinned by genetic markers.
- Looked at discordant identical twins for ASD (one had ASD, other didn’t). Found a divergence in the DNA methylation associated with some genes. Divergence in methylation pattern could correlate with incidence of ASD.
- Similarly, looked at identical twins discordant for childhood psychotic symptoms. Again, differences in pattern of DNA methylation at certain genes that could distinguish these twins. Dempster et al. (2011): Reported effect size in this particular case was relatively modest: differences in methylation between schizophrenic twins and non-schizophrenic twins were, on average, less than 10%. Associations in this field are subject to reverse causation and confounding factors. The conventional observational study at one point in time cannot determine if an epigenetic modification is a cause of the disease or if it is secondary or the result of medication use.
How can the epigenetic impact of in utero environmental diferences be implicated in twins? (Machin, 1996; Kaminsky et al., 2009; Gordon et al., 2012)
• MZ twins are exposed to different intrauterine nutritional conditions related to the formation and vascularisation of the placenta (Machin, 1996): DNA methylation profiles are less similar within pairs of monochorionic MZ twins than in pairs of dichorionic MZ twins (Kaminsky et al., 2009), potentially since MZ twins are more likely to compete for resources (Gordon et al., 2012). MZ twins are not generally subcategorised in studies based on chorionicity. Another factor in this may be unequal allocation of cells during twinning (i.e. splitting of the zygote), yet little is known about the precise mechanism of this.
How are DNA methylation patterns implicated in cancer? How can they be detected (Esteller et al., 1999), why might this not be a suitable proxy (Korshunova, 2008).
DNA methylation patterns are altered in early-stage tumours, fuelling efforts to develop diagnostic biomarkers, utilising cancer-specific alterations such as hypermethylation of promoter regions for early detection of potentially fatal tumours- these may be readily accessible using non-invasive methods- e.g. sampling blood serum (Esteller et al., 1999). However, the amount of circulating tumour DNA is rarely sufficient for detection against the epigenetic heterogeneity of normal blood, and it is doubtful whether blood is a suitable proxy for epigenetic alterations elsewhere (Korshunova et al., 2008).
What results have been found using MZ breast-cancer discordant twin samples (DOK7, 4.7yrs, Heyn et al., 2013) What are some problems with this study? 8, matching + impact of insufficient matching (e.g. smoking)
• Further support for this has also been provide using MZ twin studies which are advantageous in that they reduce genetic noise that would be present in non-MZ samples: high resolution profiling of DNA methylation in whole blood samples from breast-cancer-discordant MZ twins led to the identification of DOK7 hypermethylation as a blood-based epigenetic biomarker that could be traced in samples, on average, 4.7 years before tumour diagnosis (Heyn et al., 2013). HOWEVER, only eight twin sets were used- and it is not stated how well-matched they are environmentally. While the longitudinality of this study is a core strength, causation is not clear based on information from the report, for example smoking can cause changes in DNA methylation- if one smokes and the other didn’t, this could have an effect on the differential methylation. The methylation could be indicative of the smoking, not the presence of cancer.
